The invention relates to an implant comprising a biotoxic coating. The invention relates in particular to an implant with a titanium oxide coating containing silver ions, the silver ions being embedded into the coating by thermally sintering a precursor material. The invention further relates to a method for the production of an implant coating with a defined toxicity.
Among the problems of implant medicine is, as is known, the rejection reaction. To outwit the body's defenses, implants (for example pacemakers) are nowadays provided with biocompatible coatings on which a favorable environment for the proliferation of tissue cells predominates. This favors the implant growing in, which can additionally be supported by drugs.
Implants with a drug-releasing coating (“drug-eluting”) have been suggested in the technical literature with a variety of objectives, and they partly already exist on the market. This concerns very particularly vascular prostheses, so-called stents.
In the case of stents, the problem is known that tissue can form and/or cells can build up on the inside of the stent which counters the purpose of the stent implantation and can have life-threatening consequences for the patient, for this can lead to inflammations or the inside of the stent being overgrown. This problem is particularly acute in the case of stents that have to be placed over vessel bifurcations, since then the subordinate vessels can no longer be supplied with blood in the case of an in-stent restenosis. Therefore a biotoxic coating of the inside of the stent is desirable that prevents cells from attaching themselves by being poisoned very slowly. Other cells moving passed (for example red blood cells in the blood stream) may of course not be affected.
It was suggested to prevent these inflammation and coagulation reactions in stents by local drug release. However, randomized studies have shown that in comparison to control groups (uncoated stents) the result was not significantly different [e.g. Antonio Colombo, Jeffrey W. Moses, Marie Claude Morice et al., “Randomized Study to evaluate Sirolimus-Eluting Stents at Coronary Bifurcation Lesions”, Circulation 2004; 109:1244-1249].
At another place (galvanic) gold coating of coronary stents is reported on [Edelmann E R et al., “Gold-coated NIR stents in porcine coronary arteries”, Circulation 2001; 103:429-434]. The in vivo tests did not show any improvement in animal tests compared to the control group. There were even reports on increased inflammation and in-stent restenosis in the case of gold-coated stents [Kastrati A et al., “Increased risk of restenosis after placement of gold-coated stents: results of a randomized trial comparing gold-coated with uncoated steel stents in patients with coronary artery disease”, Circulation 2004; 101: 2478-2483].
Further studies report on carbon coatings (DLC) without any details on differences to control groups in animal tests [Galloni M, Prunotto M et al., “Carbon-coated stents implanted in porcine iliac and renal arteries: histological and histomorphic study”, J. Vasc. Radiol. 2003; 14: 1053-1061; Ralf Max Beck, “Untersuchung von Ober-flächenbeschichtungen bei Gefäβstützen zur Reduktion von Restenosen”, Thesis University of Tübingen 2001]. In an overview study, SiC, DLC and drug-coated stents were evaluated regarding to their effectiveness in reducing the in-stent restenosis rate [Babapulle M N, Eisenberg M J., “Coated stents for the prevention of restenosis: Part II”, Circulation 2002; 106: 2859-2866]. It was shown that all coatings only have a marginal influence on the restenosis rate.
A stent coating may also not be damaged or even worn off slowly by the blood constantly flowing passed. On top of this, it should show a markedly reduced biotoxicity on the stent outside precisely in order to promote the growing-in of the implant. It was therefore already suggested to provide areas having differing biocompatibility on the same implant.
The specifications WO 01/45862 A1 and US 2004/0126596 A1 reveal the possibility of a plasma treatment of implant surfaces with the goal of preventing the proliferation of specific cells thereto or to achieve an apoptosis. It is in particular also suggested to deposit suitable monomers via plasma deposition so as to form biocompatible polymer layers on the substrates. Since in principle plasma methods can only be carried out in a vacuum or a protective-gas atmosphere, it is only the implant manufacturers that can be expected to have the required equipment and process know-how.
A complication in surgical operations where a stent is implanted can also be that for example a stent has to be inserted close to a vessel bifurcation in such a way that its outside is not totally flush with the vessel wall. If this outside has now been made biocompatible by pretreatment, then this again is favorable for cells adhering at an unintended location, that is to say in the blood stream in the area of the bifurcation.
It would therefore be desirable to have implant coatings that could be modified in terms of their biotoxicity by the medical staff after their manufacture and sale using simple means. This should be possible to happen by simple admission of energy (for example light, heat, electrical discharge or similar), it being possible for a simple handheld applicator to be a possible tool for functionalizing. As an example, reference is made to UV lamps in the dental practice, using which for example tooth fillings and the like can be cured in an accelerated manner.
In another, not pre-published application the inventor proposed a method for producing substrate coatings for surface-enhanced Raman spectroscopy (SERS) where by means of a sol-gel process a titanium oxide layer containing silver ions is at first produced that forms silver nanoparticles at the surface by subsequent irradiation with—predominantly visible—light while at the same time heating.
Even though it is known from the printed patent specification U.S. Pat. No. 6,482,444 B1 that sol-gel coatings with silver-containing glass ceramics have an antibacterial effect and above all improve tissue adherence and inhibit inflammations in the case of bone and joint implants. However, silver is a known cell toxin and not to be recommended a priori for biocompatible implants.